Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression.
Reactive oxygen species (ROS) and subsequent oxidative damage may contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. ROS initiate lesion formation by inducing blood-brain barrier disruption, enhance leukocyte migration and myelin phagocytosis, and contribute to lesion persistence by mediating cellular damage to essential biological macromolecules of vulnerable CNS cells. Relatively little is known about which CNS cell types are affected by oxidative injury in MS lesions. Here, we show the presence of extensive oxidative damage to proteins, lipids, and nucleotides occurring in active demyelinating MS lesions, predominantly in reactive astrocytes and myelin-laden macrophages. Oxidative stress can be counteracted by endogenous antioxidant enzymes that confer protection against oxidative damage. Here, we show that antioxidant enzymes, including superoxide dismutase 1 and 2, catalase, and heme oxygenase 1, are markedly upregulated in active demyelinating MS lesions compared to normal-appearing white matter and white matter tissue from nonneurological control brains. Particularly, hypertrophic astrocytes and myelin-laden macrophages expressed an array of antioxidant enzymes. Enhanced antioxidant enzyme production in inflammatory MS lesions may reflect an adaptive defense mechanism to reduce ROS-induced cellular damage.
van Horssen
J
J
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. j.vanhorssen@vumc.nl
Schreibelt
G
G
Drexhage
J
J
Hazes
T
T
Dijkstra
C D
CD
van der Valk
P
P
de Vries
H E
HE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000378:metabolism*; D001253:Astrocytes / Q000201:enzymology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D016022:Case-Control Studies; D002374:Catalase / Q000378:metabolism*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D002374:Catalase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human; C496541:HMOX1 protein, human